Regulation of Mammary Gland Development and Tumorigenesis By 14-3-3 Zeta

<p>Signaling pathways that play critical roles in organ development are often aberrantly regulated during cancer initiation and progression. 14-3-3z is overexpressed in more than 40% of breast cancers and is associated with poor patient prognosis. Therefore, the function of 14-3-3z in cancer and normal mammary gland development was investigated utilizing multiple <em>in vivo</em> and <em>in vitro</em> approaches. 14-3-3z is a chaperone protein that interacts with a multitude of oncogenes and tumor suppressor genes, thereby functioning as a critical node in multiple oncogenic signaling networks. Mammary gland-specific 14-3-3z transgenic mouse models showed that 14-3-3z overexpression was sufficient to induce mammary tumorigenesis. 14-3-3z-overexpressing tumors exhibited inhibition of apoptosis and increased proliferation. Mechanistically, 14-3-3z decreased p53 expression and retained Akt-phosphorylated FKHRL in the cytosol, inhibiting transcription of pro-apoptotic genes. Additionally, 14-3-3z enhanced MAPK/c-Jun signaling leading to increased miR-221 transcription, which inhibited p27 translation, resulting in increased cell proliferation. Importantly, this 14-3-3z/miR-221/p27/proliferation axis also functions in patients' breast tumors and associates with high-grade cancers. While 14-3-3z has been identified as a crucial player in tumorigenesis, its function in normal mammary gland development remains unknown. Using 14-3-3z conventional knockout mice, we found that loss of 14-3-3z resulted in a significant delay in mammary gland ductal elongation, and decreased branch points, terminal end buds, and proliferation compared to wildtype littermates. In mammary fat pad transplantation assays, 14-3-3z-knockout (14-3-3z-/-) mammary epithelial cells (MECs) had reduced ductal outgrowth and a competitive growth disadvantage compared to wildtype (14-3-3z+/+) MECs. Interestingly, the developmental defects in 14-3-3z-/- mice correlated with a reduction in mammary stem cell (MaSC)-enriched basal population and an increase in the luminal population, indicative of decreased MaSC-self-renewal and increased luminal differentiation. Furthermore, 14-3-3z-/- mammary outgrowths presented aberrant ductal structure and deficiencies in alveogenesis and milk production whereas 14-3-3z+/+ outgrowths retained proper ductal structure and functionality. Together, our findings show that 14-3-3z overexpression plays a causal role in mammary tumorigenesis and progression through deregulation of an integrative signaling network and establishes 14-3-3z as an important player in the homeostatic growth and function of the mammary gland.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2014

Author dc:creator

• Rehman, Sumaiyah

Contributors dc:contributor

• Dihua Yu, MD, PhD
• Varsha Gandhi, PhD
• Pierre McCrea, PhD

• Breast cancer
• mammary development
• 14-3-3zeta
• ywhaz
• miR-221
• stem cells
• cell fate
• Biology
• Cancer Biology
• Developmental Biology
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/456

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1496